Maurizio Zarcone

High fasting blood glucose and obesity significantly and independently increase risk of breast cancer death in hormone receptor-positive disease.

PURPOSE We investigated the effect of fasting blood glucose and body mass index (BMI) at diagnosis on risk of breast cancer death for cases diagnosed in five Italian cancer registries in 2003-2005 and followed up to the end of 2008. METHODS For 1607 Italian women (≥15 years) with information on BMI or blood glucose or diabetes, we analysed the risk of breast cancer death in relation to glucose tertiles (≤84.0, 84.1-94.0, >94.0 mg/dl) plus diabetic and unspecified categories; BMI tertiles (≤23.4, 23.5-27.3, >27.3 kg/m(2), unspecified), stage (T1-3N0M0, T1-3N+M0 plus T4anyNM0, M1, unspecified), oestrogen (ER) and progesterone (PR) status (ER+PR+, ER-PR-, ER and PR unspecified, other), age, chemotherapy and endocrine therapy, using multiple regression models. Separate models for ER+PR+ and ER-PR- cases were also run. RESULTS Patients often had T1-3N0M0, ER+PR+ cancers and received chemotherapy or endocrine therapy; only 6% were M1 and 17% ER-PR-. Diabetic patients were older and had more often high BMI (>27 kg/m(2)), ER-PR-, M1 cancers than other patients. For ER+PR+ cases, with adjustment for other variables, breast cancer mortality was higher in women with high BMI than those with BMI 23.5-27.3 kg/m(2) (hazard ratio (HR)=2.9, 95% confidence interval (CI) 1.2-6.9). Breast cancer mortality was also higher in women with high (>94 mg/dl) blood glucose compared to those with glucose 84.1-94.0mg/dl (HR=2.6, 95% CI 1.2-5.7). CONCLUSION Our results provide evidence that in ER+PR+ patients, high blood glucose and high BMI are independently associated with increased risk of breast cancer death. Detection and correction of these factors in such patients may improve prognosis.

Expression of Wild-Type and Variant Estrogen Receptor Alpha in Liver Carcinogenesis and Tumor Progression

Although estrogen receptors (ERs) are expressed in human hepatocellular carcinoma (HCC), several clinical trials have failed to demonstrate the efficacy of antiestrogen treatment in HCC patients. Recently, the identification of several ER splicing variants has enlightened the complex nature of estrogen signaling in peripheral tissues; this may help understanding estrogen role in either nontumoral or malignant nonclassical target organs, including liver. In this work we have investigated mRNA expression of wild-type and splice variants of ERα in nontumoral, cirrhotic, and malignant human liver, as well as in HCC cell lines, using an exon-specific reverse transcription polymerase chain reaction (RT-PCR). In particular, ERα66 was detected in nontumoral and, to a lesser extent, in cirrhotic liver tissues, whereas its expression decreased or became undetectable in HCC tissues and cell lines. The ERα46 splicing variant was detected ubiquitously in all samples; interestingly, however, the ERα36 variant was inversely expressed with respect to ERα66, being highest in HepG2 cells, intermediate in Huh7 cells, and lowest in HA22T cells. It is noteworthy that aromatase was correspondingly expressed with ERα36 and inversely related to ERα66. This observation suggests that a switch from ERα66 to a predominant expression of ERα36 may be associated with development and/or progression of human HCC.

HER2/neu expression in relation to clinicopathologic features of breast cancer patients

Abstract:  We have evaluated HER2/neu expression in 1,355 breast cancer patients recruited at the Breast Cancer Registry in Palermo between January 1999 and December 2004. In this retrospective study, HER2/neu expression was related to clinicopathologic features of the disease, including tumor size, nodal and menopausal status, estrogen and progesterone receptors. Statistical analysis on all 1,355 patients showed a significant correlation between HER2/neu and nodal status (P < 0.001), and a significant association between HER2/neu overexpression and estrogen and progesterone receptors status (P < 0.001). In 194 patients without metastasis, with an average follow‐up ≥5 years, only HER2/neu 3+ and histopathologic grading G3 were significantly associated with overall survival.

Nutrition, aging and cancer: lessons from dietary intervention studies

There is convincing epidemiological and clinical evidence that, independent of aging, lifestyle and, notably, nutrition are associated with development or progression of major human cancers, including breast, prostate, colorectal tumors, and an increasingly large collection of diet-related cancers. Mechanisms underlying this association are mostly related to the distinct epigenetic effects of different dietary patterns. In this context, Mediterranean diet has been reported to significantly reduce mortality rates for various chronic illnesses, including cardiovascular diseases, neurodegenerative diseases and cancer. Although many observational studies have supported this evidence, dietary intervention studies using a Mediterranean dietary pattern or its selected food components are still limited and affected by a rather large variability in characteristics of study subjects, type and length of intervention, selected end-points and statistical analysis. Here we review data of two of our intervention studies, the MeDiet study and the DiMeSa project, aimed at assessing the effects of traditional Mediterranean diet and/or its component(s) on a large panel of both plasma and urine biomarkers. Both published and unpublished results are presented and discussed.

Application of a New Classification to a Breast Tumor Series from a Population-Based Cancer Registry : Demographic, Clinical, and Prognostic Features of Incident Cases, Palermo Province, 2002-2004

A new classification based on gene expression profiling or immunohistochemical (IHC) characteristics may replace current histopathological classifications and predict better clinical outcomes. We used IHC markers to classify incident cases ascertained by the Palermo Breast Cancer Registry (2002–2004) into four subtypes: luminal‐A (ER+ or PgR+ and HER2/neu−); luminal‐B (ER+ or PgR+, HER2/neu+); basal‐like (ER−, PgR−, HER2/neu−); and HER2+/ER− (HER2/neu+, ER−, PgR−). We evaluated HER2/neu, ER and PgR in 1300/1985 (65%) cases. The most common IHC‐subtype was luminal‐A (68%), whereas luminal‐B, basal‐like, and HER2+/ER− accounted for 14%, 13%, and 5%, respectively. IHC‐subtypes were not associated with tumor size, geographic location within the province, or menopause, but differed by NPI (P < 0.0001), grading (P < 0.0001), lymph‐node involvement (P= 0.04), metastases (P= 0.04), and TNM stage (P= 0.04). Endocrine therapy was administered to 81% of 519 postmenopausal, luminal‐A, and luminal‐B cases and to 32% of 114 postmenopausal, basal‐like, and HER2+/ER− cases.

Target therapy in HER2-overexpressing breast cancer patients.

The development of new therapeutic strategies, such as monoclonal antibodies directed against human epidermal growth factor receptor-2 (HER2), has offered new hopes for women with early breast cancer whose tumors overexpress HER2. We retrospectively analyzed the population-based data of Breast Cancer Registry of Palermo in 2004-2006, and selected 1401 invasive breast cancer cases, nonmetastatic at diagnosis, having HER2/neu oncogene expression determined. We have correlated this information to age, tumor stage at diagnosis (TNM), nodal involvement, and receptor status (ER and PgR). Survival analysis was conducted dividing the patients in two different groups according to date of diagnosis: one group diagnosed in 2004 and a second group in 2005-2006. In the 460 cases of 2004, nodal involvement, receptor status, age at diagnosis and TNM maintained a strong predictive value (p < 0.0001). In this group of patients, overall survival was significantly different according to the HER2 expression levels (p = 0.001). In the second group of patients (941 incident cases in 2005-2006) there was a statistically significant survival difference comparing patients with high levels of HER2 expression treated with trastuzumab versus those untreated (p = 0.006). Our data show that elevated levels of HER2 are a negative prognostic factor. In addition, patients overexpressing HER2 show a significant increase of overall survival when treated with trastuzumab.

Comparison of Female Breast Cancer Registration in the City and Province of Palermo With Other Italian Cancer Registries

Abstract: The aim of this study was to assess the incidence of breast cancer in women from the city and province of Palermo (Sicily) in 5 yr, 1999–2003, using a population based cancer registry approach. In the last years, a sharp increase of breast cancer incidence has been observed worldwide. Overall, direct age-standardized incidence rates were 89.3 per 100,000 person-yr, being markedly higher in Palermo City (101.0) than in Palermo Province (75.0). Results show a highly significant difference in breast cancer incidence in different areas of Sicily, particularly in the older (>50 yr) age groups and a profound difference between the metropolitan area of Palermo and the surrounding areas. The evidence of the different rates of breast cancer incidence in Palermo City and in the other small municipalities of the Palermo Province suggests a different pattern of breast cancer risk as a consequence of different lifestyle and diet modifications in the urban population of Palermo City.

Funnel plots and choropleth maps in cancer risk communication: a comparison of tools for disseminating population-based incidence data to stakeholders

Background Population-based cancer registries provide epidemiological cancer information, but the indicators are often too complex to be interpreted by local authorities and communities, due to numeracy and literacy limitations. The aim of this paper is to compare the commonly used visual formats to funnel plots to enable local public health authorities and communities to access valid and understandable cancer incidence data obtained at the municipal level. Methods A funnel plot representation of standardised incidence ratio (SIR) was generated for the 82 municipalities of the Palermo Province with the 2003–2011 data from the Palermo Province Cancer Registry (Sicily, Italy). The properties of the funnel plot and choropleth map methodologies were compared within the context of disseminating epidemiological data to stakeholders. Results The SIRs of all the municipalities remained within the control limits, except for Palermo city area (SIR=1.12), which was sited outside the upper control limit line of 99.8%. The Palermo Province SIRs funnel plot representation was congruent with the choropleth map generated from the same data, but the former resulted more informative as shown by the comparisons of the weaknesses and strengths of the 2 visual formats. Conclusions Funnel plot should be used as a complementary valuable tool to communicate epidemiological data of cancer registries to communities and local authorities, visually conveying an efficient and simple way to interpret cancer incidence data.

Estrogen signalling through amphiregulin may be implicated in human hepatocellular carcinoma.

Abstract Background: We investigated aromatase (Aro)-driven estrogen formation in non-tumoral and malignant liver tissues and cells, also in relation to expression of the estrogen receptors α and β (ERα and ERβ) and amphiregulin (AREG), aiming to gain insights into the potential role of estrogens in human hepatocellular carcinoma (HCC). Materials and methods: Chromatographic and reverse transcriptase polymerase chain reaction (RT-PCR) analyses were used to assess activity and expression of the Aro enzyme and AREG as well as the expression of wild-type and variant ERs, both in vivo and in vitro. Results: Following 24 h and 72 h incubation of liver tissues or cells with testosterone, human HCC tissues and HepG2 hepatoma cells showed elevated Aro activity (estrogen formation, respectively, of 20% and 52%–99%). By contrast, no Aro activity could be detected in non-tumoral tissues and HA22T liver cancer cells. Cirrhotic samples and Huh7 cells exhibited intermediate enzyme activity, with estrogen formation of 4% and 34%, respectively. Markedly lower or undetectable Aro mRNA levels were observed in HA22T cells and non-tumoral liver tissues compared with HepG2 cells and HCC samples. Cirrhotic specimens displayed variable transcript levels. Interestingly, no or low expression of wild-type ERα and ERβ could be observed in liver cancer cells and malignant tissues. However, ubiquitous expression of the hERα46 variant and occasional expression of the hERβ2/Cx variant were observed in cancer tissues and cells. Conclusions: It is noteworthy that the pattern of wild-type ERα was inversely related to Aro, whilst AREG expression was consistently associated with that of Aro. This combined evidence suggests that locally elevated Aro activity may increase malignant cell proliferation also through AREG signalling.

Childhood and Adolescence Cancers in the Palermo Province (Southern Italy): Ten Years (2003–2012) of Epidemiological Surveillance

Italy has one of the highest paediatric cancer incidence rates in Europe. We compared cancer incidence and survival rates in children (0–14 years) and adolescents (15–19 years) residing in Palermo Province (PP) with statistics derived from Italian and European surveillance systems. We included all incident cancer cases, malignant tumours and non-malignant neoplasm of central nervous system (benign and uncertain whether malignant or benign), detected in children and adolescents by the Palermo Province Cancer Registry (PPCR) between 2003 and 2012. A jointpoint regression model was applied. Annual Average Percentage Changes were calculated. The Besag–York-Mollie model was used to detect any cluster. The 5-year survival analysis was computed using Kaplan-Meier and actuarial methods. We identified 555 paediatric cancer incident cases (90% “malignant tumours”). No difference in incidence rates was highlighted between PPCR and Italy 26 registries and between PPCR and Southern Europe. No jointpoint or significant trend was identified and no cluster was detected. The 5-year overall survival didn’t differ between PP and the Italian AIRTUM pool. A borderline higher statistically significant survival was observed in age-group 1–4 when comparing PPCR to EUROCARE-5. The epidemiological surveillance documented in the PP was a paediatric cancer burden in line with Italy and southern Europe. The study supports the supplementary role of general population-based cancer registries to provide paediatric cancer surveillance of local communities.